Recently, the Food and Drug Administration has approved a technique called repetitive transcranial magnetic stimulation (rTMS), a noninvasive method for stimulating the brain, for the treatment of Major depressive disorder (MDD). While rTMS is an important alternative for patients who cannot tolerate medications or fail to respond to standard pharmacotherapy, like any single antidepressant treatment, rTMS fails to fully alleviate symptoms in 50- 65% of patients. One of the major stumbling blocks in improving the efficacy of rTMS efficacy is our limited understanding of how rTMS works on the brain to alleviate depression. rTMS changes neural excitability, and a typical treatment course consists of 25 rTMS sessions (1 session per day). Fifteen or more sessions are generally required before symptom changes become evident, and very little information exists about the nature and extent of induced changes (i.e., neural plasticity). The current proposal will use functional magnetic resonance imaging (fMRI) to investigate changes in neural activation in MDD patients after multiple rTMS treatments to left dorsolateral prefrontal cortex (dlPFC), targeting functional networks of the dlPFC. Forty patients with MDD will be scanned while performing a working memory task, as working memory (WM) is impaired in MDD and working memory performance reliably activates left dlPFC. Patients will be randomized to receive 20 active or 20 sham rTMS sessions, followed by fMRI scans. Using arterial spin labeling (ASL) fMRI, we will quantitate cerebral blood flow (CBF) during WM performance and during rest. As patients with MDD often overactivate left dlPFC relative to healthy control subjects, left dlPFC activation is predicted to decrease in the active rTMS group compared to the sham group, reflecting improved cortical efficiency as a specific result of the rTMS treatments. Comparison to stimulation with a sham coil should establish that observed changes are not due to placebo or time effects. Networks functionally connected to left dlPFC will also be assessed for changes as a result of active rTMS. Neural activity pre-treatment and changing with treatment will be explored as biomarkers which may moderate and mediate treatment response. The study will fill an important gap by providing information about neural changes associated with rTMS therapy, improving our understanding of the mechanism of rTMS. Impact of the proposed research: MDD is one of the most common mental disorders in the United States, and current pharmacologic treatments leave at least 1/3 of patients with persistent symptoms of depression, highlighting the need to develop and refine therapy. Improved understanding of regions and networks altered by rTMS in MDD will begin the development of a biomarker for treatment response and may identify new targets, both critical steps necessary to refine rTMS methods and improve treatment efficacy.